Tebotelimab, a PD1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study

Abstract Background: Immune checkpoint inhibitors (CPIs) targeting PD-(L)1 have become a standard of care for untreated, advanced melanoma, but demonstrated limited efficacy in mucosal melanoma. Tebotelimab, also known as MGD013, is a PD-1/LAG-3 bispecific tetravalent DART® molecule with synergistic antitumor activity shown in preclinical studies. We conducted an open-label, single-arm, multi-cohort phase 1 study (NCT04653038) to assess the efficacy and safety of tebotelimab in melanoma patients (pts) including those with CPI-naïve mucosal melanoma. Methods: The CPI-naïve cohort of this study enrolled pts with unresectable, recurrent or metastatic, mucosal or acral melanoma who had received no systemic therapy. Tebotelimab 600 mg was administered intravenously once every two weeks. The primary endpoint was overall response rate (ORR) assessed by independent radiologic review committee (IRC) per RECIST v1.1 in the efficacy analysis set consisting of pts who received ≥1 dose of tebotelimab. A post-hoc sensitivity analysis was conducted in the IRC-response evaluable set consisting of pts with IRC-assessed target lesions in the efficacy analysis set who received ≥1 post-baseline tumor assessment by IRC or died within 13 weeks after first dose. Results are reported for mucosal melanoma. Results: At data cut-off (January 19, 2022), 25 pts with mucosal melanoma were enrolled (median age, 61 years; male, 40%; ECOG 1, 40%; TNM Stage IV, 92%; metastatic, 80%). LAG-3 expression level was ≥1% in seven (28%), <1% in 15 (60%), and unknown in three (12%). PD-L1 expression was positive (CPS≥1) in three (12%), negative (CPS<1) in 19 (76%), and unknown in three (12%). All pts received ≥1 dose of tebotelimab. In the efficacy analysis set (n=25), three, three, and four pts achieved complete response (CR), partial response (PR), and stable disease (SD), respectively, leading to a confirmed ORR of 24% (95% confidence interval [CI], 9-45), with median duration of response (DOR) not reached, and a disease control rate (DCR) of 40% (95% CI, 21-61). In the IRC-response evaluable set (n=20), three, three, and four pts achieved CR, PR, and SD, respectively, leading to a confirmed ORR of 30% (95% CI, 12-54), with median DOR not reached, and a DCR of 50% (95% CI, 27-73). Immune-related treatment-emergent adverse events occurred in 11 (44%) pts, most commonly, hypothyroidism (20%), hyperthyroidism (16%), and white blood cell count decreased (12%). Grade ≥3 and serious treatment-related adverse events (TRAEs) were reported in three (12%) and four (16%) pts, respectively. TRAEs led to treatment discontinuation and death each in one (4%). Conclusions: Tebotelimab demonstrated preliminary but promising antitumor activity and a tolerable safety profile in pts with untreated, unresectable, recurrent or metastatic, mucosal melanoma. Citation Format: Si Lu, Yu Chen, Meiyu Fang, Zhengyun Zou, Di Wu, Zhiguo Luo, Jian Zhang, Jing Chen, Gang Huang, Hongming Pan, Xiubao Ren, Ying Cheng, Haichuan Su, Yuan Xin, Qiong Hua, Jianmei Hou, Jun Guo. Tebotelimab, a PD-1/LAG-3 bispecific antibody, in patients with untreated, unresectable, recurrent or metastatic, mucosal melanoma: An open-label, single-arm, Phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT208.